Boron-Containing Pharmacophore

Technology

The inventors have developed metabolically stable, borolone-containing compounds with applications in chemical biology, medicinal chemistry, and therapeutics development. The inventors characterized the oxidative stability of phenylboronic acid and two derivatives, benzoxaborole and benzoxaborolone. Benzoxaborolone is 2x10⁴-fold more stable towards oxidation by hydrogen peroxide than phenylboronic acid and benzoxaborole. Furthermore, the inventors demonstrate that benzoxaborolone can successfully inhibit activity of several enzymes, including ribonuclease A, pig liver esterase, and calf intestinal phosphatase. Overall, these findings demonstrate that usage of benzoxaborolone and other borolone-containing compounds as pharmacophores can greatly expand the potential for developing metabolically stable and effective, boron-containing drugs.

Problem Addressed

Boronic acid compounds are extensively used in chemical biology and medicinal chemistry as versatile intermediates during the synthesis of drugs and other complex molecules. However, the use of boronic acids, themselves, as pharmaceutical agents has been very limited despite their favorable properties, including low inherent toxicity and the ability to bind covalently and reversibly to proteins and carbohydrates. To date, there are only four drugs containing boron, including the proteasome inhibitor bortezomib approved for the treatment of multiple myeloma and mantle cell lymphoma. One reason for the sparsity of boronic acids in the clinic is the poor metabolic stability of boronic acids, particularly susceptibility to oxidation in aqueous contexts. Therefore, there is a need to develop metabolically stable boron-containing compounds to expand the use of boronic acids as pharmacophores.

Advantages

• Borolone-containing compounds exhibit superior metabolic stability over the more commonly used boronic acids, phenylboronic acid and benzoxaborole
• Expands the potential for development of effective, boron-containing therapeutics